We would like to investigate the mechanisms of primary human immunodeficiency disease, as related to defects in purine and pyrimidine metabolism, as well as to clarify genetic heterogeneity within this group of disorders. The recent finding that inherited deficiencies of adenosine deaminase and purine nucleoside phosphorylase (enzymes of purine salvage) can result in different forms of immunodeficiency disease will allow us to develop strategies for the discovery of mechanism by which alterations in purine and pyrimidine metabolism affect immunologic response. Appropriate manipulation of this metabolic pathway in in vivo models may lead to more rational approaches for the therapy of immunodeficiency, as well as for therapeutic manipulation of normal immune responses.